Knobloch Syndrome, Type I via the COL18A1 Gene

Knobloch syndrome, type I (KNOI; OMIM 267750) is characterized by major features of ophthalmic abnormalities and occipital encephalocele. While there is variability in clinical presentation both within and between families (Menzel et al. Hum Mutat 23:77-84, 2004), patients are uniformly affected with severe ophthalmic disease leading to vision loss (Sertié et al. Hum Mol Genet 9:2051-2058, 2000). Specific findings include high myopia, vitreoretinal degeneration with retinal detachment, and macular abnormalities. Controversy exists regarding the classification of the cranial defect as a true encephalocele or, alternatively, as an occipital scalp defect. Seaver et al. (Am J Med Genet 46:203-208, 1993) suggested in some cases the abnormality found associated with Knobloch syndrome is a scalp defect, but its occurrence should nonetheless alert clinicians to the possibility of a significant underlying midline defect. Patients with Knobloch syndrome have been found to have normal to above normal intelligence (Seaver et al., 1993). Neuronal migration defects have been reported for this disorder in two families (Kliemann et al. Am J Med Genet 119A:15-19, 2003). Endostatin is a 20 kDa carboxy terminal proteolytic cleavage product of type XVIII collagen that has been shown to be a potent antiangiogenic and antitumor compound (O’Reilly et al. Cell 88:277-285, 1997). An endostatin polymorphism has been shown to be a risk factor for prostate cancer (Iughetti et al. Cancer Res 61:7375-7378, 2001).

Knobloch syndrome is an autosomal recessive disorder caused by variants in the COL18A1 gene (Sertié et al. Hum Mol Genet 9:2051-2058, 2000). Evidence has been presented for a second causative locus (Menzel et al. Hum Mutat 23:77-84, 2004; Suzuki et al. Am J Hum Genet 71:1320-1329, 2002), although a second gene has not yet been identified. Almost all COL18A1 variants reported are nonsense or splice site variants. One COL18A1 missense variant (p.Asp1437Asn) located within the endostatin region has been reported to be causative for Knobloch syndrome (Menzel et al. 2004). Three isoforms of the alpha chain of collagen type XVIII are coded by exons 1-43 of the COL18A1 gene (OMIM 120328) located on chromosome 21q22.3. Isoforms 2 and 3, but not 1, are expressed in the retina (Sertié et al. 2000; Suzuki et al. 2002).

Test sensitivity should be high in patients with clinical features consistent with Knobloch syndrome. Suzuki et al. (Am J Hum Genet 71:1320-1329, 2002) found two causative alleles in five of eight patients.

This test provides full coverage of all coding exons of the COL18A1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).